The goal of the proposed research is to gain insight into the prolonged effects of stress on the brain with a focus on the relationship between stress and drug addiction. Stress is known to exacerbate a variety of pathological states, including drug addiction, and is thought to cause changes in brain chemistry that can impact subsequent behavior. Animal models have shown that social defeat stress results in increased responsiveness to drug effects, particularly psychostimulants. This is known as cross-sensitization, which can last for several months. Sensitization is thought to reflect alterations in the brain that occur during the process of addiction. Both stress, including social defeat stress, and psychostimulants activate the dopamine reward system (the mesocorticolimbic system) in the brain. As such, it is thought that stress- induced changes within the mesocorticolimbic system are related to stress-induced sensitization. To date, the exact mechanism of persistent stress-induced sensitization has not yet been fully defined. The proposed project will investigate the role of brain-derived neurotrophic factor (BDNF) in short- and long- term social defeat stress-induced sensitization. The first goal will be to characterize the time-course and region-specificity of BDNF changes in the mesocorticolimbic system after social defeat stress using immunohistochemistry and in situ hybridization methodology. The second aim will entail inhibiting or enhancing BDNF production in neurons of the ventral tegmental area, a critical structure for sensitization, during social defeat stress in order to investigate subsequent effect on long-term cross-sensitization to amphetamine: In order to achieve this end, virus-mediated gene delivery methods will be employed. The third goal will use pharmacological tools to evaluate the role of BDNF release in the ventral tegmental area during social defeat stress in short- and long-term cross-sensitization. Drug abuse remains a pervasive public health issue, and epidemiology has shown a strong correlation between stress and prevalence of drug abuse. The interplay of biology and environment is an important factor in addiction, and the work proposed herein will help elucidate some of the mechanisms that may influence addictive processes.